Mitogen-activated protein kinase signaling and its association with oxidative stress and apoptosis in lead-exposed hepatocytes

Abstract

Lead toxicity has become a serious public health concern all over the world. Previous studies have shown that lead induces biochemical and structural changes in liver. However, although lead is known to alter liver functions, the underlying molecular mechanisms of hepatotoxicity are not yet clear. We hypothesized that a correlation exists between oxidative stress, apoptosis and mitogen-activated protein kinases (MAPKs) in lead-exposed liver. Wistar rats were treated with 0, 0.5%, and 1% lead acetate for 3d, 14d, and 35d and sacrificed the next day. On 4d, oxidative stress and apoptosis were correlated with downregulated expressions of ERK1/2 and p38-MAPKα/β, and upregulated expressions of JNK1/3 in males. In females, the correlation was with downregulated expressions of ERK1/2 and upregulated expressions of p38-MAPKα/β and JNK1/3. On 15d, the correlation was observed with upregulated expressions of p38-MAPKα/β in males and downregulated expressions of p38-MAPKα/β in females. In both sexes, a correlation was observed with upregulated expressions of ERK1/2 and JNK1/3 in 1% groups. On 36d, the correlation was observed with downregulated expressions of p38-MAPKα/β in males and their upregulated expressions in females. Time-dependent increase in lipid peroxidation on 15d and 36d correlated with upregulated expressions of p38-MAPKα/β in females and ERK1/2 in 1% groups in both sexes. The lower dose induced more apoptosis up to 15d in females and the higher dose induced in males on 36d. Generally, the female livers had more p38-MAPKα/β than the male livers. On 36d, the female livers showed more p38-MAPKα/β and JNK1/3 than the male livers. In conclusion, although not clearly defined, a correlation exists among oxidative stress, apoptosis, and the MAPKs in lead-exposed hepatocytes. The sex-dependent effects may be due to differences in hormonal or other physiological mechanisms. In lead-exposed hepatocytes, the apoptosis may be induced via oxidative stress-mediated alterations in the MAPKs.

Antagonistic Efficacy of Luteolin against Lead Acetate Exposure-Associated with Hepatotoxicity is Mediated via Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Activities

“…Hepatocyte apoptosis occurs through two main pathways: the extrinsic pathway, which depends on signals from the death receptor, and the intrinsic pathway, which is triggered by intracellular stimuli. In agreement with previous studies, Pb exposure was associated with an induction of cell apoptotic mediators and a marked disturbance in the gene expression of apoptosis-regulating proteins [7,47,66]. The apoptosis induced by Pb exposure may result from the damage of the mitochondrial membrane allowing the release of cytochrome-c and caspase-activating factors into the cytosol.…”

“…Lead is a multi-organ toxicant that affects vital organs, such as the brain, liver, kidney, and testis, causing various diseases and cancers [5][6][7][8][9][10]. Hepatotoxicity induced by Pb was previously reported to be related to the destruction of liver structure and loss of function [11,12].…”

The detrimental effects of lead on human and animal health

“…In another experiment, with the objective to investigate the gender, dose and time-dependent manner of Pb-induced oxidative stress besides observing time and dose-dependent increase in liver MDA levels; the correlation between oxidative stress, apoptosis, and mitogen-activated protein kinases (MAPKs) in hepatocytes was observed. The authors concluded that apoptosis might be induced via oxidative stress-mediated alterations in MAPKs [ 74 ]. Kilikdar et al .…”

Probit analysis of comparative assays on toxicities of lead chloride and lead acetate to in vitro cultured human umbilical cord blood lymphocytes

“…Age related impairments in behavioral functions had been linked to lead poisoning that caused changes in neurotransmitter levels in brain tissue (Chand et al ., 2014 ). Lead induced biochemical and structural changes occur in liver causing cataclysmic alterations by oxidative stress, apoptosis and mitogen activated protein kinase (Mujaibel & Kilarkaje, 2013 , Samaraghandian et al ., 2013 ). Particularly, oxidative stress had been reported to be one of several important possible mechanisms in lead toxicity (Shalan et al ., 2005 ) with the generation of hydroxyl radical, hydrogen peroxide, superoxide anion and lipid peroxidase, etc .…”